(a) Field
The subject matter disclosed generally relates to novel hybrid molecules of dietary agents being multi-targeting agents effective against both hormone-sensitive and hormone-independent cancers.
(b) Related Prior Art
The androgen receptor (AR) is a critical mediator of prostate cancer. This has provided the rationale for the use of androgen ablation therapy, which is done via surgical or chemical castration to reduce testicular androgens and/or antiandrogens that bind AR and antagonize the function of androgens. However, most patients progress to a lethal castration-resistant form of the disease called castration-resistant prostate cancer (CRPC). Prognosis of patients with established CRPC is very poor, with median overall survival <2 years. It is now firmly established that most CRPC remain hormone driven. Intensive research reveals that CRPC cells have amazing versatile capability in counteracting our attempts to block the AR signalling, using multiple escape routes to maintain AR signaling. Once prostate cancer becomes castration-resistant (also referred to as hormone-refractory or androgen-independent), the hormonal therapy with current antiandrogens is not effective. The development of AR mutations is an important mechanism that accounts for the development of resistance to current antiandrogens, such as flutamide and bicalutamide. One particular mutation is the T877A in the ligand-binding domain of AR, which actually results in paradoxical activation by hydroxyflutamide, an active metabolite of anti-androgen flutamide. The T877A mutation promotes prostate cancer cell growth and cell survival. The W741L and W741C mutant ARs were found to be activated by another anti-androgen bicalutamide (Casodex). Bicalutamide has been found to promote tumor growth in a novel androgen-dependent prostate xenograft model derived from a bicalutamide-treated patient. Significantly, the T877A mutation has been found in patients who were treated with flutamide and eventually became refractory to the treatment, and W741C is found in a patient who experienced treatment failure with bicalutamide.
The helix-12 (H12) at the AR ligand-binding domain (AR-LBD) plays a critical role in AR transactivation. On binding of androgen, such as di-hydrotestosterone (DHT), at the hormone-binding pocket, H12 is repositioned to cover the pocket, forming a functional activation function 2 surface. In the crystal structures of the T877A and W741L mutated AR-LBD in complex with hydroxyflutamide and bicalutamide, respectively, the H12 is in the agonistic form as expected, since in the presence of these mutations both drugs act as an agonist in the mutant ARs. This correlates with the clinical ‘antiandrogen withdrawal syndrome’, in which patients whose disease progress during antiandrogen therapy experience a fall in serum prostate-specific antigen after discontinuation of the therapy.
It has been recognized that one way to develop novel AR antagonist is to design chemical compound that has a core structure to bind the hormone-binding pocket and an extending bulky arm to displace H12. Such a strategy has been successful in the design of estrogen receptor and several other nuclear receptor antagonists. To date, reports of anti-androgens capable of circumventing multiple mutant ARs are limited. There are two recent reports that disclosed the efforts to develop anti-androgen against resistant mutant ARs: i) McGinley et al (J. Am. Chem. Soc. 2007, 129, 3822-3823) reported identification of bicalutamide derivative such as PLM1 that at a low micromolar concentration shows potent activity in suppressing DHT-induced transcriptional activation of wild-type, W741L and T877A mutant ARs; ii) To develop anti-androgen bearing a bulky chain, Cantin et al. (J Biol Chem 2007, 282, 30910-30919) reported synthesis of a set of DHT-derived molecules bearing various bulky chains, such as EM5744. Unexpectedly, EM-5744 turned out to be a potent agonist of the AR. Crystallographic study indicated the H12 of AR ligand-binding domain is indeed at the agonistic position.
The development of novel anti-androgens that are active against multiple mutant ARs represents an attractive strategy to combat antiandrogen resistance.